Toll-like receptors in tumor immunotherapy

Chrystal M. Paulos, Andrew Kaiser, Claudia Wrzesinski, Christian S. Hinrichs, Lydie Cassard, Andrea Boni, Pawel Muranski, Luis Sanchez-Perez, Douglas C. Palmer, Zhiya Yu, Paul A. Antony, Luca Gattinoni, Steven A. Rosenberg, Nicholas P. Restifo

Research output: Contribution to journalReview articlepeer-review

Abstract

Lymphodepletion with chemotherapeutic agents or total body irradiation (TBI) before adoptive transfer of tumor-specific T cells is a critical advancement in the treatment of patients with melanoma. More than 50% of patients that are refractory to other treatments experience an objective or curative response with this approach. Emerging data indicate that the key mechanisms underlying how TBI augments the functions of adoptively transferred T cells include (a) the depletion of regulatory T cells (Treg) and myeloid-derived suppressor cells that limit the function and proliferation of adoptively transferred cells; (b) the removal of immune cells that act as "sinks" for homeostatic cytokines, whose levels increase after lymphodepletion; and (c) the activation of the innate immune system via Toll-like receptor 4 signaling, which is engaged by microbial lipopolysaccharide that translocated across the radiation-injured gut. Here, we review these mechanisms and focus on the effect of Toll-like receptor agonists in adoptive immunotherapy. We also discuss alternate regimens to chemotherapy or TBI, which might be used to safely treat patients with advanced disease and promote tumor regression.

Original languageEnglish (US)
Pages (from-to)5280-5289
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number18
DOIs
StatePublished - Sep 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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